Climate change and epigenetic biomarkers in allergic and airway diseases
Authors: Andres Cardenas, Raj Fadadu, Supinda Bunyavanich
Journal: Journal of Allergy and Clinical Immunology (2023)

Human epigenetic variation is associated with both environmental exposures and allergic diseases and can potentially serve as a biomarker connecting climate change with allergy and airway diseases. In this narrative review, we summarize recent human epigenetic studies examining exposure to temperature, precipitation, extreme weather events, and malnutrition to discuss findings as they relate to allergic and airway diseases. Temperature has been the most widely studied exposure, with the studies implicating both short-term and long-term exposures with epigenetic alterations and epigenetic aging. Few studies have examined natural disasters or extreme weather events. The studies available have reported differential DNA methylation of multiple genes and pathways, some of which were previously associated with asthma or allergy. Few studies have integrated climate-related events, epigenetic biomarkers, and allergic disease together. Prospective longitudinal studies are needed along with the collection of target tissues beyond blood samples, such as nasal and skin cells. Finally, global collaboration to increase diverse representation of study participants, particularly those most affected by climate injustice, as well as strengthen replication, validation, and harmonization of measurements will be needed to elucidate the impacts of climate change on the human epigenome. Human epigenetic variation is associated with both environmental exposures and allergic diseases and can potentially serve as a biomarker connecting climate change with allergy and airway diseases. In this narrative review, we summarize recent human epigenetic studies examining exposure to temperature, precipitation, extreme weather events, and malnutrition to discuss findings as they relate to allergic and airway diseases. Temperature has been the most widely studied exposure, with the studies implicating both short-term and long-term exposures with epigenetic alterations and epigenetic aging. Few studies have examined natural disasters or extreme weather events. The studies available have reported differential DNA methylation of multiple genes and pathways, some of which were previously associated with asthma or allergy. Few studies have integrated climate-related events, epigenetic biomarkers, and allergic disease together. Prospective longitudinal studies are needed along with the collection of target tissues beyond blood samples, such as nasal and skin cells. Finally, global collaboration to increase diverse representation of study participants, particularly those most affected by climate injustice, as well as strengthen replication, validation, and harmonization of measurements will be needed to elucidate the impacts of climate change on the human epigenome. 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The epigenome lies at the intersection between environmental risk factors and human diseases. Epigenetic alterations refer to changes in gene expression that are not directly related to variation in the underlying genetic code. They allow us to better characterize early biomarkers of impact from environmental exposures and their connection to human health.16Harb H. Renz H. Update on epigenetics in allergic disease.J Allergy Clin Immunol. 2015; 135: 15-24Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,17Potaczek D.P. Harb H. Michel S. Alhamwe B.A. Renz H. Tost J. Epigenetics and allergy: from basic mechanisms to clinical applications.Epigenomics. 2017; 9: 539-571Crossref PubMed Scopus (191) Google Scholar Epigenetic marks are tissue and cell type specific, which can yield insights into underlying changes and responses in specific organs. In epidemiologic studies, once DNA is extracted (often from a mixed population of cells in a human subject), methylation can be measured after bisulfite treatment using sequencing or microarrays (eg, the 450K or 850K/EPIC Illumina arrays [Illumina, San Diego, Calif]). The most commonly studied epigenetic modification in human studies is DNA methylation of cytosine nucleotides (cytosine-phosphate-guanine dinucleotide [CpG] sites).16Harb H. Renz H. Update on epigenetics in allergic disease.J Allergy Clin Immunol. 2015; 135: 15-24Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,17Potaczek D.P. Harb H. Michel S. Alhamwe B.A. Renz H. Tost J. 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Although temperature, humidity, and precipitation have been examined in human epigenetic studies less commonly than air pollution has,19Melén E. Koppelman G.H. Vicedo-Cabrera A.M. Andersen Z.J. Bunyavanich S. Allergies to food and airborne allergens in children and adolescents: role of epigenetics in a changing environment.Lancet Child Adolesc Health. 2022; 6: 810-819Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,25Ji H. Biagini Myers J.M. Brandt E.B. Brokamp C. Ryan P.H. Khurana Hershey G.K. Air pollution, epigenetics, and asthma.Allergy Asthma Clin Immunol. 2016; 12: 51Crossref PubMed Scopus (45) Google Scholar research using plant and animal models have shown that these climatic factors affect DNA methylation and gene expression in multiple ways.26Gugger P.F. Fitz-Gibbon S. PellEgrini M. Sork V.L. 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Thermal stress alters expression of genes involved in one carbon and DNA methylation pathways in Atlantic cod embryos.Comp Biochem Physiol A Mol Integr Physiol. 2014; 173C: 17-27Crossref PubMed Scopus (35) Google Scholar The most recent systematic review regarding climate and human epigenetic modifications was conducted in 2020; it identified 15 genes with methylation status associated with temperature, including genes associated with asthma (eg, TLR2 and NOS2).31Xu R. Li S. Guo S. Zhao Q. Abramson M.J. Li S. et al.Environmental temperature and human epigenetic modifications: a systematic review.Environ Pollut. 2020; 259113840Crossref Scopus (30) Google Scholar However, it did not examine other climatic factors. The objective of this article is to provide the first review of studies investigating epigenetic mechanisms related to multiple climatic factors, including temperature, humidity, and precipitation, and climate change-associated exposures, such as natural disasters and malnutrition, as well as how they may relate to allergic diseases. We also discuss strengths, challenges, and opportunities for future research on this topic. For this narrative review, we conducted an online search for original research articles published on the topic of epigenetics and climatic exposures. This search included multiple epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, as well as various environmental exposures related to climate and climate change, such as temperature, precipitation, and natural disasters. The search was performed in 3 databases—PubMed, Web of Science, and EMBASE—for articles published between January 1, 2000, and August 1, 2023, by using a combination of Medical Subject Headings (MeSH) terms that are listed in Table I. The findings from relevant articles from this search are discussed in the following sections organized by environmental exposure, and we provide interpretation regarding their connections to allergic and immunologic outcomes. Data on epigenetic markers and/or associated gene annotations related to climate exposures were extracted from studies, when available, and included in Table E1 (in the Online Repository at www.jacionline.org). For the section on temperature, we focused on recently published studies that were not evaluated in the most recent systematic review on this topic, which was published in 2020.31Xu R. Li S. Guo S. Zhao Q. Abramson M.J. Li S. et al.Environmental temperature and human epigenetic modifications: a systematic review.Environ Pollut. 2020; 259113840Crossref Scopus (30) Google Scholar Although air pollution is a major cause of climate change, studies regarding direct associations of air pollution and DNA methylation were excluded from this review because they have previously been reviewed extensively.25Ji H. Biagini Myers J.M. Brandt E.B. Brokamp C. Ryan P.H. Khurana Hershey G.K. Air pollution, epigenetics, and asthma.Allergy Asthma Clin Immunol. 2016; 12: 51Crossref PubMed Scopus (45) Google Scholar,32Saenen N.D. Martens D.S. Neven K.Y. Alfano R. Bové H. Janssen B.G. et al.Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?.Clin Epigenetics. 2019; 11: 124Crossref PubMed Scopus (103) Google Scholar,33Rider C.F. Carlsten C. Air pollution and DNA methylation: effects of exposure in humans.Clin Epigenetics. 2019; 11: 131Crossref PubMed Scopus (168) Google ScholarTable IDescription of the strategy used to search for recent articlesParameterDetailsDates of searchJanuary 1, 2000, to August 1, 2023DatabasesPubMed, EMBASE, and Web of ScienceSearch terms"epigenetics," "epigenome," "methylome," "DNA methylation," "histone," "non-coding RNA," "temperature," "thermal," "global warming," "climate," "radiation," "humidity," "hurricane," "flooding," "heat," "wildfires," "extreme weather," "extreme temperature," "heat wave," "blizzard," "thunderstorm," "tornado," "malnutrition," "famine" Open table in a new tab The goal of environmental epigenetic studies is to investigate how and when environmental exposures contribute to epigenetic variation, which can affect the prevalence, incidence, and severity of human diseases. It is important to note that environmental exposures, including climate-related factors, at different stages of life (such as in utero, early childhood, and adulthood), can differentially affect the epigenome and to also note that genetic variation can also play a role in affecting variability of DNA methylation.34Li S. Ye Z. Mather K.A. Nguyen T.L. Dite G.S. Armstrong N.J. et al.Early life affects late-life health through determining DNA methylation across the lifespan: a twin study.EBioMedicine. 2022; 77103927Abstract Full Text Full Text PDF Scopus (9) Google Scholar In particular, in utero exposure is a susceptible window, as epigenetic programming of cells, organs, and tissues is established during this period.35Kohli R.M. Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation.Nature. 2013; 502: 472-479Crossref PubMed Scopus (1157) Google Scholar Additionally, ancestry-specific methylation quantitative trait loci (meQTL) support the inclusion of ancestrally diverse and multiethnic populations in epigenetic studies. Epigenetic modifications can also reflect disease progression, so the longitudinal collection of samples is key to distinguishing biomarkers of exposure from biomarkers of disease that might be characterized in cross-sectional studies (Fig 1). There are several methodologies that are used in environmental epigenetics research, and we have defined commonly used terms found in this review and in the literature listed in Table II. The first step involves the extraction of DNA from a population of cells from specific tissues, such as whole blood, the skin, or nasal or bronchial epithelium. Once the DNA is processed, it can be analyzed by using a variety of methods, including methylation arrays.36Rauluseviciute I. Drabløs F. Rye M.B. DNA methylation data by sequencing: experimental approaches and recommendations for tools and pipelines for data analysis.Clin Epigenetics. 2019; 11: 193Crossref PubMed Scopus (52) Google Scholar The 450K and 850K EPIC BeadChips have commonly been used in epigenome-wide association studies (EWASs) to systematically measure the methylation of CpG sites across the human genome in large epidemiologic cohorts.37Campagna M.P. Xavier A. Lechner-Scott J. Maltby V. Scott R.J. Butzkueven H. et al.Epigenome-wide association studies: current knowledge, strategies and recommendations.Clin Epigenetics. 2021; 13: 214Crossref PubMed Scopus (39) Google Scholar Then, several statistical and bioinformatic approaches are used to test for associations between methylation status of CpG sites and phenotypes and/or exposures of interest. The most common approach is to test each CpG individually across all DNA methylation measurements, often referred to as a differentially methylated position. This approach can be complemented by testing entire regions, defined by proximity or correlation structure, referred to as a differentially methylated region (DMR) with multiple CpGs. This technique has been used to systematically assess the relationship between multiple different environmental exposures, asthma, and allergic diseases.38Cardenas A. Fadadu R.P. Koppelman G.H. Epigenome-wide association studies of allergic disease and the environment.J Allergy Clin Immunol. 2023; 152: 582-590Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar A more targeted approach involves selecting certain genes a priori (eg, using specific primers or an array specific for a panel of genes related to inflammation) and analyzing methylation of the relevant CpG sites. An example of this approach is the study of how farm milk exposure contributed to increased methylation of FOXP3 in regulatory T (Treg) cells, which was associated with decreased atopic sensitization and asthma in childhood.39Lluis A. Depner M. Gaugler B. Saas P. Casaca V.I. Raedler D. et al.Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood.J Allergy Clin Immunol. 2014; 133: 551-559.e10Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar A newer methodology is the use of epigenetic clocks, which are DNA methylation biomarkers of biologic aging found to be predictors of morbidity and mortality.40Horvath S. Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing.Nat Rev Genet. 2018; 19: 371-384Crossref PubMed Scopus (1238) Google Scholar These biomarkers estimate an epigenetic age that is predictive of an individual's chronologic age. Deviation between both measures is referred to as epigenetic age acceleration (EAA), which is a strong risk factor for mortality and morbidity (including due to allergic diseases) and shown to be influenced by environmental factors. For example, 1 study found that cigarette smoking is associated with increased EAA among adults,41Cardenas A. Ecker S. Fadadu R.P. Huen K. Orozco A. McEwen L.M. et al.Epigenome-wide association study and epigenetic age acceleration associated with cigarette smoking among Costa Rican adults.Sci Rep. 2022; 12: 4277Crossref PubMed Scopus (15) Google Scholar and another showed that greater EAA in childhood is associated with higher odds of having atopy and food allergen sensitization.23Peng C. Cardenas A. Rifas-Shiman S.L. Hivert M.F. Gold D.R. Platts-Mills T.A. et al.Epigenetic age acceleration is associated with allergy and asthma in children in Project Viva.J Allergy Clin Immunol. 2019; 143: 2263-2270.e14Abstract Full Text Full Text PDF PubMed Scopus (39) Google ScholarTable IIDefinition of common terms used in epigenetics researchTermDefinitionEWASA comprehensive genome-wide testing of epigenetic marks and how they are associated with phenotypes or exposures of interestCpG siteDNA dinucleotides of cytosine followed by guanine in which the cytosine nucleotide may have a methyl group added by DNA methyltransferase, which can alter gene transcriptionDMRAn entire genomic region composed of multiple CpG sites with differential DNA methylation across samplesNon-coding RNAsFunctional molecules of RNA that are not translated to proteins but can affect gene expression and protein functioningEpigenetic clocksStatistical calculators that use methylation data at certain CpG sites to derive an epigenetic age, which is a marker of biologic aging that is correlated with morbidity and mortalityEAADeviations between epigenetic and chronologic age calculated as the residuals from when each DNA methylation clock output is regressed on the chronologic age of each participantmeQTLsSingle-nucleotide polymorphisms associated with DNA methylation variation of a CpG sitemeQTL, Methylation quantitative trait locus. Open table in a new tab meQTL, Methylation quantitative trait locus. Most environmental epigenetics studies on allergy and asthma have focused on cigarette smoke and air pollution as common exposures of interest. Although their results have been discordant, many EWASs have found that these exposures are frequently associated with differential methylation of CpG sites near or in the promoters of AHRR, FOXP3, and IL4.33Rider C.F. Carlsten C. Air pollution and DNA methylation: effects of exposure in humans.Clin Epigenetics. 2019; 11: 131Crossref PubMed Scopus (168) Google Scholar,42Knopik V.S. Maccani M.A. Francazio S. McGeary J.E. The epigenetics of maternal cigarette smoking during pregnancy and effects on child development.Dev Psychopathol. 2012; 24: 1377-1390Crossref PubMed Scopus (203) Google Scholar,43Mukherjee S. Dasgupta S. Mishra P.K. Chaudhury K. Air pollution-induced epigenetic changes: disease development and a possible link with hypersensitivity pneumonitis.Environ Sci Pollut Res Int. 2021; 28: 55981-56002Crossref PubMed Scopus (19) Google Scholar This is relevant because DNA methylation in these regions could influence gene expression, as shown in studies of smoking and AHRR methylation.44Reynolds L.M. Wan M. Ding J. Taylor J.R. Lohman K. Su D. et al.DNA Methylation of the aryl hydrocarbon receptor repressor associations with cigarette smoking and subclinical atherosclerosis.Circ Cardiovasc Genet. 2015; 8: 707-716Crossref PubMed Scopus (92) Google Scholar,45Tsai P.C. Glastonbury C.A. Eliot M.N. Bollepalli S. Yet I. Castillo-Fernandez J.E. et al.Smoking induces coordinated DNA methylation and gene expression changes in adipose tissue with consequences for metabolic health.Clin Epigenetics. 2018; 10: 126Crossref PubMed Scopus (79) Google Scholar These findings have emerged mostly from cross-sectional study designs, which are limited because the timing of exposure and disease development and the directionality of DNA methylation variability are less clear. Nonetheless, new methodologic advancements in the field of environmental epigenetics show promise for elucidating the relationship between climatic factors and allergic diseases to improve disease prevention and treatment. Epidemiologic studies on climate change and epigenetics have focused on extreme weather events, temperature, and factors aggravated by climate change, such as famine and drought. These factors have frequently been tested for cross-sectional associations with DNA methylation isolated from leukocytes. In the following sections, we discuss studies from our search and place their results in the context of allergic and airway diseases. We found 1 study that examined microRNAs (miRNAs) as the epigenetic outcome of interest, whereas the rest of the studies measured DNA methylation; none of them investigated histone modifications. Exposures to high temperature, both chronic and acute, are associated with increased morbidity and mortality, and various epigenetic research methodologies have been used to investigate this relationship (Table III).46Ebi K.L. Capon A. Berry P. Broderick C. Dear R de Havenith G. et al.Hot weather and heat extremes: health risks.Lancet. 2021; 398: 698-708Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar There might be several pathways linking temperature fluctuations to allergic disease (Table IV). For example, extreme heat might affect airway responsiveness by activating certain transient receptor potential cation channels and stimulating cholinergic reflex pathways.47Millqvist E. TRP channels and temperature in airway disease—clinical significance.Temperature. 2015; 2: 172-177Crossref PubMed Scopus (16) Google Scholar Additionally, increased membrane fluidity and disruption of transmembrane structural proteins can increase risk for an inflammatory response. Regarding temperature-related epigenetic alterations, a systematic review of studies published before 2020 summarized results from 7 research articles and identified 15 candidate genes31Xu R. Li S. Guo S. Zhao Q. Abramson M.J. Li S. et al.Environmental temperature and human epigenetic modifications: a systematic review.Environ Pollut. 2020; 259113840Crossref Scopus (30) Google Scholar; in the following sections, we discuss findings from more recent studies on this topic.Table IIISummary of epigenetic studies on temperature and precipitationStudy titleAuthors (y)LocationPopulationExposureEpigenetic end pointKey finding(s)Temperature EWAS of Short-Term Temperature FluctuationsBased on Within-Sibship Analyses in Australian FemalesWu et al (2023)AustraliaAdult female twins and their sisters in the AMDTSSShort-term changes in temperatureDNA methylation (EWAS) of peripheral leukocytes analyzed with the 450K BeadChip-Temperature changes were associated with differential methylation of 14 CpGs and 70 DMRs mapping to 68 genes linked to human diseases Associations between Medium- and Long-Term Exposure to Air Temperature and EAANi et al (2023)Augsburg, GermanyKORALa